tbuckley/cabot-search huggingface dataset:
Abstract 2177: Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells
Authors: Juan Apiz-Saab, Alex Muir
Journal: Cancer Research (2022)

Abstract Arginine is an amino acid critical for various cellular processes, not only protein synthesis but also metabolism of other essential metabolites, like polyamines, as well as a signaling factor for pathways such as the growth regulator mTOR. Previously, our group measured arginine levels in the interstitial fluid of tumors (TIF) of pancreatic ductal adenocarcinoma (PDAC) murine models and found extremely low arginine levels (2-5 uM) in the tumor microenvironment (TME). Despite near complete absence of this critical nutrient in the TME, pancreatic tumors exhibit aggressive growth. We have sought to understand both how the PDAC TME becomes arginine limited and how PDAC cells adapt to proliferate in the absence of arginine. Using genetically engineered mice, we find that arginase activity in the myeloid compartment of PDAC tumors is responsible for arginine depletion in the TME. Staining of Arg1+ myeloid populations in human PDAC samples suggest a similar mechanism reduces arginine availability in human PDAC tumors as well. We then leveraged our newfound knowledge of PDAC TIF composition to develop a novel ex vivo cell culture media formulation with physiologically relevant nutrient levels and monitored arginine acquisition pathways using isotope tracing and metabolomics assays to determine how PDAC cells cope with arginine deprivation. Under TME nutrient conditions, PDAC cells consume available citrulline and use it to produce arginine by de novo synthesis. Starving cells of citrulline or genetically perturbing arginosuccinate synthase (ASS1), key enzyme in arginine biosynthesis, significantly reduces PDAC cellular arginine and proliferative capacity. Immunohistochemical analysis of both human and mouse PDAC tumors indicates that the de novo arginine synthesis pathway is highly expressed in PDAC but not in untransformed pancreas, suggesting a key role for this pathway in PDAC progression. Altogether, we find that myeloid-derived arginase challenges PDAC cells by limiting arginine availability and suggest that de novo arginine synthesis may be a critical metabolic pathway that enables PDAC tumors to cope with this metabolic challenge. Citation Format: Juan Apiz-Saab, Alex Muir. Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2177.
Abstract 3537: Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade
Authors: Svena Verma, Inna Serganova, Sadna Budhu, Lauren Dong, Myat Ko, Levi Mangarin, Taha Merghoub, Jedd Wolchok, Roberta Zappasodi
Journal: Cancer Research (2022)

Abstract Preferential engagement in glycolysis is a hallmark of cancer cells and contributes to the progression and metastasis of many tumor types, including melanoma and triple-negative breast cancer (TNBC). Tumor reliance on glycolysis is emerging as a mechanism of resistance to immunotherapy, due in part to lactate-mediated immunosuppression and competition for glucose between effector T cells and tumor cells within the tumor microenvironment. Elevated serum lactate dehydrogenase (LDH) levels are associated with poor outcomes in cancer patients, and we observed that serum lactate and LDH levels correlate with primary tumor burden in mice. We recently demonstrated that genetic dampening of LDH subunit A in 4T1 TNBC results in improved and long-lasting anti-tumor responses to CTLA-4 blockade in mice. Therefore, we hypothesize that combining LDH inhibitors (LDHi) with CTLA-4 blockade will be an effective strategy to combat resistance to anti-CTLA-4 therapy. Since activated T cells rely on glycolysis, we first determined that glycolytic cancers overexpress LDH (compared with immune cells) by analyzing single-cell transcripts from patient melanoma biopsies. LDHA gene expression is significantly higher in malignant cells than infiltrating CD8+ T cells, and we replicated these findings at the protein level in whole cell lysate from B16-F10 melanoma and 4T1 TNBC tumor cells and tumor-antigen specific T cells in vitro. We show that LDHi reduces tumor lactate production and glucose consumption without inhibiting anti-tumor T-cell killing in vitro. The anti-tumor effect of LDH inhibition requires adaptive immunity, as daily treatment with LDHi results in reduced tumor burden in immunocompetent but not immune-deficient mice. Finally, we show that targeting LDH in combination with CTLA-4 blockade is more effective in slowing B16-F10 growth compared with CTLA-4 blockade alone, and that this combination promotes effector T cell activation while destabilizing regulatory T cell function. Citation Format: Svena Verma, Inna Serganova, Sadna Budhu, Lauren Dong, Myat Ko, Levi Mangarin, Taha Merghoub, Jedd Wolchok, Roberta Zappasodi. Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3537.
Abstract CT231: Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy
Authors: Lidia Delrieu, Anne-Sophie Hamy, Florence Coussy, Amyn Kassara, Bernard Asselain, Juliana Antero, Paul De Villèle, Elise Dumas, Nicolas Forstmann, Julien Guérin, Judicael Hotton, Christelle Jouannaud, Maud Milder, Armand Leopold, Adrien Sedeaud, Pauline Soibinet, Jean-François Toussaint, Vincent Vercamer, Enora Laas, Fabien Reyal
Journal: Cancer Research (2022)

Abstract Introduction: Breast cancer (BC) has particular characteristics in young women, with diagnosis at more advanced stages, a poorer prognosis and highly aggressive tumors. In NeoFit, we will use an activity tracker to identify and describe various digital profiles (heart rate, physical activity, and sleep patterns) in women below the age of 45 years on neoadjuvant chemotherapy for BC.Methods/Analysis: NeoFit is a prospective, national, multicenter, single-arm open-label study. It will include 300 women below the age of 45 years treated with neoadjuvant chemotherapy for BC. Participants will be asked to wear a Withing Steel HR activity tracker round the clock for 12 months. The principal assessments will be performed at baseline, at the end of neoadjuvant chemotherapy and at 12 months. We will evaluate clinical parameters, such as toxicity and the efficacy of chemotherapy, together with quality of life, fatigue, and parameters relating to lifestyle and physical activity. The women will complete REDCap form questionnaires via a secure internet link.Discussion: In this study, the use of an activity tracker will enable us to visualize changes in the lifestyle of young women on neoadjuvant chemotherapy for BC, over the course of a one-year period. This exploratory study will provide crucial insight into the digital phenotypes of young BC patients on neoadjuvant chemotherapy and the relationship between these phenotypes and the toxicity and efficacy of treatment. This trial will pave the way for interventional studies involving sleep and physical activity interventions. Citation Format: Lidia Delrieu, Anne-Sophie Hamy, Florence Coussy, Amyn Kassara, Bernard Asselain, Juliana Antero, Paul De Villèle, Elise Dumas, Nicolas Forstmann, Julien Guérin, Judicael Hotton, Christelle Jouannaud, Maud Milder, Armand Leopold, Adrien Sedeaud, Pauline Soibinet, Jean-François Toussaint, Vincent Vercamer, Enora Laas, Fabien Reyal. Digital phenotyping in young breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT231.
Cyclocreatine Suppresses Creatine Metabolism and Impairs Prostate Cancer Progression
Authors: Rachana Patel, Catriona A. Ford, Lisa Rodgers, Linda K. Rushworth, Janis Fleming, Ernest Mui, Tong Zhang, David Watson, Victoria Lynch, Gillian Mackay, David Sumpton, Owen J. Sansom, Johan Vande Voorde, Hing Y. Leung
Journal: Cancer Research (2022)

Abstract Prostate cancer is the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of the tumor suppressors PTEN and Sprouty2 (SPRY2), we identified enhanced creatine metabolism as a central component of progressive disease. Creatine treatment was associated with enhanced cellular basal respiration in vitro and increased tumor cell proliferation in vivo. Stable isotope tracing revealed that intracellular levels of creatine in prostate cancer cells are predominantly dictated by exogenous availability rather than by de novo synthesis from arginine. Genetic silencing of creatine transporter SLC6A8 depleted intracellular creatine levels and reduced the colony-forming capacity of human prostate cancer cells. Accordingly, in vitro treatment of prostate cancer cells with cyclocreatine, a creatine analog, dramatically reduced intracellular levels of creatine and its derivatives phosphocreatine and creatinine and suppressed proliferation. Supplementation with cyclocreatine impaired cancer progression in the PTEN- and SPRY2-deficient prostate cancer GEMMs and in a xenograft liver metastasis model. Collectively, these results identify a metabolic vulnerability in prostate cancer and demonstrate a rational therapeutic strategy to exploit this vulnerability to impede tumor progression. Significance: Enhanced creatine uptake drives prostate cancer progression and confers a metabolic vulnerability to treatment with the creatine analog cyclocreatine.
Abstract 5888: Trends in incidence of gallbladder cancer in all 50 United States from 2001 to 2018
Authors: Syed A. Raza, Wilson L. Costa, Aaron P. Thrift
Journal: Cancer Research (2022)

Abstract Background: Gallbladder cancer (GBC) is an aggressive malignancy of the gastrointestinal system that is historically more common among racial/ethnic minority populations in the US. We investigated trends in GBC incidence rates in all 50 states from 2001 to 2018, overall and stratified by race/ethnicity, sex, and different regions. Methods: Age-standardized incidence rates and trends in adults aged ≥35 years were calculated using data from the U.S. Cancer Statistics registry. We used joinpoint regression to compute annual percent changes (APC) and average annual percent changes (AAPC) and corresponding 95% confidence intervals (CI) for both sexes and used eleven 5-year age groups (35-39 years through 85+ years). Race/ethnic groups were classified as non-Hispanic Whites and Blacks (NHWs and NHBs), Hispanics, American Indians/Alaska Natives, and Asians and Pacific Islanders. Results: Overall, the age-standardized incidence rate for GBC decreased by 0.3% annually between 2001 and 2018 (95% CI -0.5%, -0.1%). However, secular trends varied by age-group, sex and race/ethnicity. APC increased among individuals aged 45-54 years from 1.2% to 1.4% but decreased among those who were ≥ 75 years (-0.7% to -1.6% per year). While GBC incidence rates were stable among men between 2001 and 2014, incidence rates decreased by over 2% per year between 2014 and 2018 (APC, -2.1%; 95%CI: -3.9, -0.3). GBC incidence remained relatively stable between 2001 and 2018 among women. While GBC rates declined in other racial/ethnic groups, the rates increased by 1.4% annually among non-Hispanic Blacks (NHBs) between 2001 and 2018 (APC=1.4%; 95%CI: 0.9%, 2.0%). Among NHBs, increasing trends were also noted in Northeast, Midwest, and South regions of US. Conclusions: The study shows increasing incidence trends for GBC in the US among NHBs from 2001-2018 compared to decreasing trends among other race/ethnic groups. The results also point to the need for studying equitable detection and treatment of underlying risk factors for GBC. Citation Format: Syed A. Raza, Wilson L. Costa, Aaron P. Thrift. Trends in incidence of gallbladder cancer in all 50 United States from 2001 to 2018 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5888.
Abstract 3921: Precise spatial multiplexing for immune profiling in clinical FFPE tumor samples with ChipCytometry࣪
Authors: Kevin Gamber, Arne Christians, Jennifer Brooks, Karen Kwarta, Crystal Winkeler
Journal: Cancer Research (2022)

Abstract Highly multiplexed spatial biomarker analysis has the potential to inform the discovery of novel biomarkers and treatments with the potential to improve clinical outcomes. Clinical diagnoses and treatment decisions have traditionally been made with spatially resolved techniques like immunohistochemistry, that offer a wealth of information about cellular morphology and the spatial context of cells but are limited to a single plex. Newer technologies, such as single-cell RNA sequencing, identify cell subpopulations within tissue but do not capture their spatial distribution or intercellular interactions in situ. Here we present the analysis of clinical FFPE tumor samples using ChipCytometry, a novel precise spatial multiplexing technology that offers high-plex biomarker analysis, without compromising spatial context. ChipCytometry combines iterative immuno-fluorescent staining with high-dynamic range imaging to facilitate quantitative phenotyping with single-cell resolution. Standard FCS files are generated from multichannel OME-TIFF images, enabling identification of cellular phenotypes via flow cytometry-like hierarchical gating. In this study, we identify and quantify immune and epithelial cell phenotypes and subtypes in melanoma and non-small cell lung cancer FFPE samples. The results show precise expression levels for each marker in the assay in each individual cell in the sample, while maintaining spatial information about each cell. Spatial analysis of the samples reveals quantifiable heterogeneity of immune cell infiltration within the tumor samples, demonstrating the utility of the ChipCytometry platform for the in-depth immune profiling in clinical FFPE samples. -Bruker Confidential- Citation Format: Kevin Gamber, Arne Christians, Jennifer Brooks, Karen Kwarta, Crystal Winkeler. Precise spatial multiplexing for immune profiling in clinical FFPE tumor samples with ChipCytometry࣪ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3921.
Abstract 5424: Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN
Authors: Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul M. Diderichsen, Huub J. Kleijn, Kosalaram Goteti, Andreas Schroeder, Karthik Venkatakrishnan
Journal: Cancer Research (2022)

Abstract Xevinapant, an antagonist of Inhibitor of Apoptosis Proteins (IAPs) showed significant improvement in locoregional control at 18 months (LRC18; primary endpoint), overall survival (OS) and progression-free survival (PFS) at an oral dose of 200 mg/day given on days 1-14 every 3 weeks in combination with CRT versus CRT with placebo in a phase II trial in patients with high-risk LA SCCHN (NCT02022098). In the dose escalation (DE) part of NCT02022098, 200 mg/day was the maximum tolerated dose and a trend of dose-response for efficacy in the 100-300 mg/day dose range was observed. The phase III TrilynX study of xevinapant plus CRT in patients with LA SCCHN is currently enrolling (NCT04459715). Here we present the integrated rationale for the recommended phase III dose (RP3D) of xevinapant 200 mg/day based on all available clinical and preclinical data and modeling and simulation (M&amp;S). At the RP3D, ~95% of the patients are projected to have free trough concentrations above in vitro IC50 for cIAP1 degradation (a pharmacodynamic [PD] marker), based on a population (pop) PK M&amp;S. In patients, average free concentration over the dosing interval at RP3D is similar to that associated with maximal efficacy in preclinical SCCHN models. Pop PK/PD M&amp;S suggests that maximal cIAP1 degradation is maintained in PBMCs with 100-200 mg/day doses during the 14-day dosing period, with a trend of dose-response for the partial cIAP1 degradation at the end of the 3-week cycle. Exposure response (E-R) analyses were conducted based on the pooled datasets of DE and randomized parts of study NCT02022098 (n=62 treated with xevinapant). Logistic regressions showed that probabilities of LRC18, overall response, complete response, and the composite safety endpoint of “mucositis and/or dysphagia” increase with increasing exposure (p&amp;lt;0.05). Statistically significant E-R relationships were not discernible for any other evaluated safety endpoints or for PFS, OS, or duration of LRC. However, patients in higher exposure subgroups showed a longer duration of LRC. In summary, integration of preclinical pharmacology, clinical efficacy and safety profiles, clinical PK/PD, popPK, and E-R analyses support the RP3D selection of xevinapant at 200 mg/day administered on days 1-14 every 3 weeks with concomitant CRT, allowing for successive dose reductions to 150 mg and 100 mg for management of toxicities. Citation Format: Yulia Vugmeyster, Abhigyan Ravula, Elisabeth Rouits, Paul M. Diderichsen, Huub J. Kleijn, Kosalaram Goteti, Andreas Schroeder, Karthik Venkatakrishnan. Selection of RP3D of xevinapant in combination with CRT in patients with LA SCCHN [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5424.
A Young Man With Syncope
Authors: Asad J. Torabi, Mark Kauth, Takeki Suzuki
Journal: JAMA Cardiology (2022)

A man in his early 20s presented with suspected syncope and shaking with no significant medical history. He denied confusion afterward but did not feel well with nausea, flushing, chest tightness, and a rapid heart rate. What would you do next?
Abstract 3917: A novel multifunctional role for Hsp70 in binding post-translational modifications on client proteins
Authors: None Nitika, Jake Kline, Luca Fornelli, Andrew Truman
Journal: Cancer Research (2022)

Abstract Hsp70 interactions are critical for cellular viability and the response to stress. Previous attempts to characterize Hsp70 interactions have been limited by their transient nature and inability of current technologies to distinguish direct vs bridged interactions. We report the novel use of cross-linking mass spectrometry (XL-MS) to comprehensively characterize the budding yeast Hsp70 protein interactome. In doing so, we have uncovered not only a new set of Hsp70 client proteins but show that these clients bind at multiple sites on Hsp70, including the N-terminal NBD. Notably, many of the Hsp70 interactions with client proteins are in close proximity to biologically important post translational modifications (PTMs). Using this approach, we have gained fundamental new insights into Hsp70 function, including definitive evidence of Hsp70 self-association as well as multi-point interaction with its client proteins. In addition to identifying a novel set of direct Hsp70 interactors which can be used to probe chaperone function in cells, we have also identified a suite of PTM-associated Hsp70 interactions. The majority of these PTMs have not been previously reported and appear to be critical in the regulation of client protein function. These data indicate that one of the mechanisms by which PTMs contribute to protein function is by facilitating interaction with chaperones. Taken together, we propose that XL-MS analysis of chaperone complexes may be used as a unique way to identify biologically important PTMs on client proteins. All in all, our data suggest that our XL-MS approach to chaperone interactome characterization can also be used as a novel way to identify biologically important and previously unknown PTMs on client proteins. Citation Format: Nitika, Jake Kline, Luca Fornelli, Andrew Truman. A novel multifunctional role for Hsp70 in binding post-translational modifications on client proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3917.
Lysophosphatidylserines derived from microbiota in Crohn’s disease elicit pathological Th1 response
Authors: Yuriko Otake-Kasamoto, Hisako Kayama, Toshihiro Kishikawa, Shinichiro Shinzaki, Taku Tashiro, Takahiro Amano, Mizuki Tani, Takeo Yoshihara, Bo Li, Haruka Tani, Li Liu, Akio Hayashi, Daisuke Okuzaki, Daisuke Motooka, Shota Nakamura, Yukinori Okada, Hideki Iijima, Kiyoshi Takeda, Tetsuo Takehara
Journal: The Journal of Experimental Medicine (2022)

Microbiota alteration and IFN-γ–producing CD4+ T cell overactivation are implicated in Crohn’s disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites derived from dysbiotic microbiota that induce enhanced Th1 responses and exaggerate colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied by a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprogramming, thereby eliciting aberrant effector responses in both human and mouse IFN-γ–producing CD4+ T cells. Administration of LysoPS into two mouse colitis models promoted large intestinal inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hyporesponsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota promote Th1-mediated intestinal pathology.